Project Summary/Abstract Our goal is to advance our understanding and ability to treat Alzheimer's disease. Our lab discovered that tau reduction can prevent A?-induced activation of GSK3?, a kinase that is activated by many AD-relevant pathomechanisms and has been implicated in the hyperphosphorylation of tau. We will determine which of these mechanisms activate GSK3? in a tau-dependent manner and whether the activation involves direct interactions between tau and GSK3?. To prevent tau-dependent GSK3? activation, we propose to reduce overall tau levels. Tau reduction can prevent cognitive decline and neurodegeneration in mouse models of AD. We found that blocking the rho-associated protein kinase (ROCK) pathway reduces tau levels in primary cells and in adult mouse brain. To further explore this therapeutic strategy, we will use a new ROCK inhibitor that has high potency and good brain penetration in mouse models.